Antibacterial agents

ABSTRACT

Naphthyridine and related derivatives useful in the treatment of bacterial infections in mammals, particularly humans, are disclosed herein.

This application is a 371 of PCT/US06/02280 filed Jan. 24, 2006, whichclaims the benefit of U.S. Provisional Application No. 60/646,798 filedJan. 25, 2005.

FIELD OF THE INVENTION

This invention relates to novel compounds, compositions containing them,their use as antibacterials, and processes for their preparation.

BACKGROUND OF THE INVENTION

The emergence of pathogens resistant to known antibiotic therapy isbecoming a serious global healthcare problem (Chu, et al., (1996) J.Med. Chem., 39: 3853-3874). Thus, there is a need to discover new broadspectrum antibiotics useful in combating multidrug-resistant organisms.Importantly, it has now been discovered that certain compounds haveantibacterial activity, and, therefore, may be useful for the treatmentof bacterial infections in mammals, particularly in humans. WO0125227,WO0240474, WO0207572, WO04024712, WO04024713, WO9937635, WO0021948,WO0021952, WO0043383, WO0078748, WO0107433, WO0107432, WO0208224,WO0224684, WO0250061, WO0250040, WO0256882, WO0296907, WO03087098,WO03010138, WO03064431, WO03064421, WO04002992, and WO0400249 disclosequinoline and/or naphthyridine derivatives having antibacterialactivity.

SUMMARY OF THE INVENTION

This invention comprises compounds of the formula (I), as describedhereinafter, which are useful in the treatment of bacterial infections.This invention is also a pharmaceutical composition comprising acompound according to formula (I) and a pharmaceutically acceptablecarrier. This invention is also processes for the preparation ofcompounds of formula (I), as well as processes for the preparation ofintermediates useful in the synthesis of compounds of formula (I). Thisinvention is also novel intermediates useful in the preparation ofantibacterial agents. This invention is also a method of treatingbacterial infections in mammals, particularly in humans.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a compound of formula (I) or a pharmaceuticallyacceptable salt, solvate or derivative thereof:

wherein:

Z₁, Z₃, and Z₄ are independently N or CR^(1a);

Z₂, Z₅, and Z₆ are each CR^(1a);

A is CR₂R₃;

W₁, W₂, and W₃ are each CR₄R₅;

B is CR₉R₁₀ or a bond;

X is O, S, NR₁₁, or CR₄R₅;

R₁ and R^(1a) are independently at each occurrence hydrogen; cyano;halogen; hydroxy; (C₁₋₆)alkoxy unsubstituted or substituted by(C₁₋₆)alkoxy, hydroxy, amino, piperidyl, guanidino or amidino any ofwhich is unsubstituted or N-substituted by one or two (C₁₋₆)alkyl, acyl,(C₁₋₆)alkylsulphonyl, CONH₂, hydroxy, (C₁₋₆)alkylthio, heterocyclylthio,heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or(C₁₋₆)alkylsulphonyloxy; (C₁₋₆)alkyl; (C₁₋₆)alkylthio; trifluoromethyl;trifluoromethoxy; nitro; azido; acyl; acyloxy; acylthio;(C₁₋₆)alkylsulphonyl; (C₁₋₆)alkylsulphoxide; arylsulphonyl;arylsulphoxide; or an amino, piperidyl, guanidino or amidino groupunsubstituted or N-substituted by one or two (C₁₋₆)alkyl, acyl or(C₁₋₆)alkylsulphonyl groups; or R₁ and R^(1a) of Z₂ together formethylenedioxy;

R₂ is hydrogen; halogen; hydroxy; acyloxy; or (C₁₋₆)alkoxy; and R₃ ishydrogen;

R₄, R₅, R₆, R₇, R₉, and R₁₀ are independently at each occurrencehydrogen; thiol; (C₁₋₆)alkylthio; halogen; trifluoromethyl; azido;(C₁₋₆)alkyl; (C₂₋₆)alkenyl; (C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl;(C₂₋₆)alkenylcarbonyl; (C₂₋₆)alkenyloxycarbonyl; aralkyl; aryl;heterocyclyl; heterocyclylalkyl; hydroxy; NR^(1b)R^(1b′);(C₁₋₆)alkylsulphonyl; (C₂₋₆)alkenylsulphonyl; or (C₁₋₆)aminosulphonylwherein the amino group is optionally and independently substituted byhydrogen, (C₁₋₆)alkyl, (C₂₋₆)alkenyl or aralkyl;

R₈ is hydrogen; halogen; hydroxyl; or (C₁₋₆)alkyl;

R₁₁ is hydrogen, trifluoromethyl; (C₁₋₆)alkyl; (C₂₋₆)alkenyl;(C₁₋₆)alkoxycarbonyl; (C₁₋₆)alkylcarbonyl; (C₂₋₆)alkenyloxycarbonyl;aryl; aralkyl; (C₃₋₈)cycloalkyl; heterocyclyl; or heterocyclylalkyl;

R^(1b) and R^(1b)′ are independently at each occurrence hydrogen;(C₁₋₆)alkyl; aralkyl; aryl; heterocyclyl; heterocyclylalkyl; or togetherwith the nitrogen that they are attached form an aziridine, azetidine,pyrrolidine, piperidine or hexamethyleneimine ring (wherein saidaziridine, azetidine, pyrrolidine, piperidine or hexamethyleneimine ringare optionally substituted with from 1 to 3 substituents selected fromhalogen, hydroxy; cyano; nitro; (C₁₋₆)alkyl; and aryl);

R₁₂ is UR₁₃;

U is CH₂; C(═O); or SO₂;

R₁₃ is a substituted or unsubstituted bicyclic, carbocyclic, orheterocyclic ring system (A):

containing up to four heteroatoms in each ring in which at least one ofrings (a) and (b) is aromatic;

X¹ is C or N when part of an aromatic ring or CR₁₄ when part of a nonaromatic ring;

X² is N, NR₁₅, O, S(O)_(n), CO or CR₁₄ when part of an aromatic ornon-aromatic ring or may in addition be CR₁₆R₁₇ when part of a nonaromatic ring;

n is independently at each occurrence 0, 1, or 2;

X³ and X⁵ are independently N or C;

Y¹ is a 0 to 4 atom linker group each atom of which is independentlyselected from N, NR₁₅, O, S(O)_(n), CO and CR₁₄ when part of an aromaticor non-aromatic ring or may additionally be CR₁₆R₁₇ when part of a nonaromatic ring,

Y² is a 2 to 6 atom linker group, each atom of Y² being independentlyselected from N, NR₁₅, O, S(O)_(n), CO and CR₁₄ when part of an aromaticor non-aromatic ring or may additionally be CR₁₆R₁₇ when part of a nonaromatic ring;

R₁₄, R₁₆ and R₁₇ are at each occurrence independently selected from: H;(C₁₋₄)alkylthio; halo; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy;hydroxy(C₁₋₄)alkyl; mercapto(C₁₋₄)alkyl; (C₁₋₄)alkoxy; trifluoromethoxy;nitro; cyano; carboxy; amino or aminocarbonyl unsubstituted orsubstituted by (C₁₋₄)alkyl;

R₁₅ is at each occurrence independently hydrogen; trifluoromethyl;(C₁₋₄)alkyl unsubstituted or substituted by hydroxy, carboxy,(C₁₋₄)alkoxy, (C₁₋₆)alkylthio, halo or trifluoromethyl; (C₂₋₄)alkenyl;or aminocarbonyl wherein the amino group is optionally substituted with(C₁₋₄)alkyl; or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, this invention provides a compound of formula (I)wherein Z₁ and Z₄ are N; and Z₃ is CR^(1a).

In some embodiments, this invention provides a compound of formula (I)wherein R₁ is OCH₃.

In some embodiments, this invention provides a compound of formula (I)wherein R^(1a) is at each occurrence independently hydrogen; halogen; orcyano.

In some embodiments, this invention provides a compound of formula (I)wherein R₂ is hydrogen.

In some embodiments, this invention provides a compound of formula (I)wherein R₄, R₅, R₆, R₇, R₉, and R₁₀ are each independently selected fromhydrogen, hydroxyl, halogen, and (C₁₋₆)alkyl.

In some embodiments, this invention provides a compound of formula (I)wherein R₄, R₅, R₆, R₇, R₉, and R₁₀ are each hydrogen.

In some embodiments, this invention provides a compound of formula (I)wherein B is a bond.

In some embodiments, this invention provides a compound of formula (I)wherein R₈ is hydrogen.

In some embodiments, this invention provides a compound of formula (I)wherein R₁₁ is hydrogen.

In some embodiments, this invention provides a compound of formula (I)wherein U is CH₂.

In some embodiments, this invention provides a compound of formula (I)wherein R₁₃ is 4H-Pyrido[3,2-b][1,4]thiazin-3-oxo-6-yl;4H-Pyrido[3,2-b][1,4]oxazin-3-oxo-6-yl; or2,3-Dihydro-[1,4]dioxino[2,3-c]-pyridin-6-yl.

In some embodiments, this invention describes a compound of formula (I)wherein X is O.

In some embodiments, this invention describes a compound of formula (I)wherein Z₁ and Z₄ are N; Z₃ is CR^(1a); R₁ is OCH₃; R^(1a) of Z₂, Z₃,and Z₅ is hydrogen; R^(1a) of Z₆ is hydrogen or fluorine; R₂ ishydrogen; R₄ and R₅ of W₁ and W₂ are each hydrogen; R₄ of W₃ is hydrogenor hydroxyl; R₅ of W₄ is hydrogen; R₆ and R₇ are each hydrogen; R₈ ishydrogen;

In some embodiments, this invention describes a compound of formula (I)wherein Z₁ and Z₄ are N; Z₃ is CR^(1a); R₁ is OCH₃; R^(1a) of Z₂, Z₃,and Z₅ is hydrogen; R^(1a) Of Z₆ is hydrogen or fluorine; R₂ ishydrogen; R₄ and R₅ of W₁ and W₂ are each hydrogen; R₄ of W₃ is hydrogenor hydroxyl; R₅ of W₄ is hydrogen; R₆ and R₇ are each hydrogen; R₈ ishydrogen; X is O; B is a bond; and R₁₁ is hydrogen.

In some embodiments, this invention describes a compound of formula (I)wherein Z₁ and Z₄ are N; Z₃ is CR^(1a); R₁ is OCH₃; R^(1a) of Z₂, Z₃,and Z₅ is hydrogen; R^(1a) of Z₆ is hydrogen or fluorine; R₂ ishydrogen; R₄ and R₅ of W₁ and W₂ are each hydrogen; R₄ of W₃ is hydrogenor hydroxyl; R₅ of W₄ is hydrogen; R₆ and R₇ are each hydrogen; R₈ ishydrogen; X is O; B is a bond; R₁₁ is hydrogen; U is CH₂ and R₁₃ is4H-Pyrido[3,2-b][1,4]thiazin-3-oxo-6-yl;4H-Pyrido[3,2-b][1,4]oxazin-3-oxo-6-yl; or2,3-Dihydro-[1,4]dioxino[2,3-c]-pyridin-6-yl.

In some embodiments, this invention provides a compound of formula (I)wherein the compound is3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one;6-{[((1R,5R,6R)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one;6-{[((1R,5R,6S)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;6-{[((1R,5R,6R)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-oneor a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, this invention provides a pharmaceuticalcomposition comprising a compound of formula (I) or any other structuralembodiment of the invention, and a pharmaceutically acceptable carrier

In some embodiments, this invention provides a method of treatingbacterial infections in mammals which comprises administering to amammal in need thereof an effective amount of a compound of formula (I)or any other structural embodiment of the invention.

In some embodiments, the mammal to be treated is a human.

In some embodiments, this invention describes compounds of formula Iwherein the (a) and (b) rings of R₁₃ are both aromatic as demonstratedby the following non-limiting examples: 1H-pyrrolo[2,3-b]-pyridin-2-yl,1H-pyrrolo[3,2-b]-pyridin-2-yl, 3H-imidazo[4,5-b]-pyrid-2-yl,3H-quinazolin-4-one-2-yl, benzimidazol-2-yl,benzo[1,2,3]-thiadiazol-5-yl, benzo[1,2,5]-oxadiazol-5-yl,benzofur-2-yl, benzothiazol-2-yl, benzo[b]thiophen-2-yl,benzoxazol-2-yl, chromen-4-one-3-yl, imidazo[1,2-a]pyridin-2-yl,imidazo-[1,2-a]-pyrimidin-2-yl, indol-2-yl, indol-6-yl,isoquinolin-3-yl, [1,8]-naphthyridine-3-yl, oxazolo[4,5-b]-pyridin-2-yl,quinolin-2-yl, quinolin-3-yl, quinoxalin-2-yl, indan-2-yl,naphthalen-2-yl, 1,3-dioxo-isoindol-2yl, benzimidazol-2-yl,benzothiophen-2-yl, 1H-benzotriazol-5-yl, 1H-indol-5-yl,3H-benzooxazol-2-one-6-yl, 3H-benzooxazol-2-thione-6-yl,3H-benzothiazol-2-one-5-yl, 3H-quinazolin-4-one-2-yl,3H-quinazolin-4-one-6-yl, 4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl,benzo[1,2,3]thiadiazol-6-yl, benzo[1,2,5]thiadiazol-5-yl,benzo[1,4]oxazin-2-one-3-yl, benzothiazol-5-yl, benzothiazol-6-yl,cinnolin-3-yl, imidazo[1,2-a]pyridazin-2-yl,imidazo[1,2-b]pyridazin-2-yl, pyrazolo[1,5-a]pyrazin-2-yl,pyrazolo[1,5-a]pyridin-2-yl, pyrazolo[1,5-a]pyrimidin-6-yl,pyrazolo[5,1-c][1,2,4]triazin-3-yl, pyrido[1,2-a]pyrimdin-4-one-2-yl,pyrido[1,2-a]pyrimidin-4-one-3-yl, quinazolin-2-yl, quinoxalin-6-yl,thiazolo[3,2-a]pyrimidin-5-one-7-yl, thiazolo[5,4-b]pyridin-2-yl,thieno[3,2-b]pyridin-6-yl, thiazolo[5,4-b]pyridin-6-yl,4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl,1-oxo-1,2-dihydro-isoquinolin-3-yl, thiazolo[4,5-b]pyridin-5-yl,[1,2,3]thiadiazolo[5,4-b]pyridin-6-yl, 2H-isoquinolin-1-one-3-yl.

In yet other embodiments, R₁₃ is defined by a non-aromatic (a) ring andaromatic (b) ring as illustrated by the following non-limiting examples:(2S)-2,3-dihydro-1H-indol-2-yl, (2S)-2,3-dihydro-benzo[1,4]dioxine-2-yl,3-(R,S)-3,4-dihydro-2H-benzo[1,4]thiazin-3-yl,3-(R)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl,3-(S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-yl,2,3-dihydro-benzo[1,4]dioxan-2-yl,3-substituted-3H-quinazolin-4-one-2-yl,2,3-dihydro-benzo[1,4]dioxan-2-yl,1-oxo-1,3,4,5-tetrahydrobenzo[c]azepin-2-yl. In still other embodiments,R₁₃ is defined by an aromatic (a) ring and a non aromatic (b) ring asillustrated by the following non-limiting examples:1,1,3-trioxo-1,2,3,4-tetrahydro-1/⁶-benzo[1,4] thiazin-6-yl,benzo[1,3]dioxol-5-yl, 2,3-dihydro-benzo[1,4]dioxin-6-yl,2-oxo-2,3-dihydro-benzooxazol-6-yl, 4H-benzo[1,4]oxazin-3-one-6-yl(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl),4H-benzo[1,4]thiazin-3-one-6-yl(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl),4H-benzo[1,4]oxazin-3-one-7-yl,4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepine-7-yl,5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-6-yl,benzo[1,3]dioxol-5-yl,2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]thiazin-7-yl,3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl,2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl,2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl,6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidin-2-yl,3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl,2-oxo-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazin-7-yl,2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl,6-oxo-6,7-dihydro-5H-8-thia-1,2,5-triaza-naphthalen-3-yl,3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,3-substituted-3H-benzooxazol-2-one-6-yl,3-substituted-3H-benzooxazole-2-thione-6-yl,3-substituted-3H-benzothiazol-2-one-6-yl,2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl,3,4-dihydro-2H-benzo[1,4]thiazin-6-yl,3,4-dihydro-1H-quinolin-2-one-7-yl,3,4-dihydro-1H-quinoxalin-2-one-7-yl,6,7-dihydro-4H-pyrazolo[1,5-a]pyrimidin-5-one-2-yl,5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl,2-oxo-3,4-dihydro-1H-[1,8]naphthyridin-6-yl,3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl.

Unless otherwise defined, the term “alkyl” when used alone or whenforming part of other groups (such as the ‘alkoxy’ group) includessubstituted or unsubstituted, straight or branched chain alkyl groupscontaining the specified range of carbon atoms. For example, the term“(C₁₋₆)alkyl” include methyl, ethyl, propyl, butyl, iso-propyl,sec-butyl, tert-butyl, iso-pentyl, and the like.

The term “alkenyl” means a substituted or unsubstituted alkyl group ofthe specified range of carbon atoms, wherein one carbon-carbon singlebond is replaced by a carbon-carbon double bond. For example, the term“(C₂₋₆)alkenyl” include ethylene, 1-propene, 2-propene, 1-butene,2-butene, and isobutene, and the like. Both cis and trans isomers areincluded.

The term “cycloalkyl” refers to substituted or unsubstituted carbocyclicsystem of the specified range of carbon atoms, which may contain up totwo unsaturated carbon-carbon bonds. For example, the term“(C₃₋₇)cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, and cycloheptyl.

The term “alkoxy” refers to an O-alkyl radical where the alkyl groupcontains the specified range of carbon atoms and is as defined herein.

The term “acyl” refers to a C(═O)alkyl or a C(═O)aryl radical. In someembodiments, the alkyl group contains 13 or less carbons; in someembodiments 10 or less carbon atoms; in some embodiments 6 or lesscarbon atoms; and is as otherwise defined. Aryl is as defined herein.

The term “alkylcarbonyl” refers to a (C₁₋₆)alkyl(C═O)(C₁₋₆)alkyl groupwherein alkyl is as otherwise defined herein.

The term “alkylsulphonyl” refers to a SO₂alkyl radical wherein the alkylgroup contains the specified range of carbon atoms and is as definedherein.

The term “alkylthio” refers to a Salkyl wherein the alkyl group containsthe specified range of carbon atoms and is as defined herein.

The term “aminosulphonyl” refers to a SO₂N radical wherein the nitrogenis substituted as specified.

The term “aminocarbonyl” refers to a carboxamide radical wherein thenitrogen of the amide is substituted as defined.

The term “heterocyclylthio” refers to a S-heterocyclyl radical whereinthe heterocyclyl moiety is as defined herein.

The term “heterocyclyloxy” refers to an O-heterocyclyl radical whereinheterocyclyl is as defined herein.

The term “arylthio” refers to an S-aryl radical wherein aryl is asdefined herein.

The term “aryloxy” refers to an O-aryl radical wherein aryl is asdefined herein.

The term “acylthio” refers to a S-acyl radical wherein acyl is asdefined herein.

The term “acyloxy” refers to an O-acyl radical wherein acyl is asdefined herein.

The term “alkoxycarbonyl” refers to a CO₂alkyl radical wherein the alkylgroup contains the specified range of carbon atoms and is as definedherein.

The term “alkenyloxycarbonyl” refers to a CO₂alkyl radical wherein thealkenyl group contains the specified range of carbon atoms and is asdefined herein.

The term “alkylsulphonyloxy” refers to an O—SO₂alkyl radical wherein thealkyl group contains the specified range of carbon atoms and is asdefined herein.

The term “arylsulphonyl” refers to a SO₂aryl radical wherein aryl is asherein defined.

The term “arylsulphoxide” refers to a SOaryl radical wherein aryl is asdefined herein.

Unless otherwise defined, suitable substituents for any alkyl, alkoxy,alkenyl, and cycloalkyl groups includes up to three substituentsselected from the group consisting of hydroxy, halogen, nitro, cyano,carboxy, amino, amidino, sulphonamido, unsubstituted (C₁₋₃)alkoxy,trifluromethyl, and acyloxy.

Halo or halogen includes fluoro, chloro, bromo and iodo.

The term “haloalkyl” refers to an alkyl radical containing the specifiedrange of carbon atoms and is as otherwise defined herein, which isfurther substituted with 1-3 halogen atoms.

The term “haloalkoxy” refers to an alkoxy radical of the specified rangeand as defined herein, which is further substituted with 1-3 halogenatoms.

The term “hydroxyalkyl” refers to an alkyl group as defined herein,further substituted with a hydroxy group.

Unless otherwise defined, the term “heterocyclic” or “heterocyclyl” asused herein includes optionally substituted aromatic and non-aromatic,single and fused, mono- or bicyclic rings suitably containing up to fourhetero-atoms in each ring selected from oxygen, nitrogen and sulphur,which rings may be unsubstituted or C-substituted by, for example, up tothree groups selected from (C₁₋₄)alkylthio; halo; (C₁₋₄)haloalkoxy;(C₁₋₄)haloalkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy; hydroxy,(C₁₋₄)alkyl; (C₁₋₄)thioalkyl; (C₁₋₄)alkoxy; nitro; cyano, carboxy;(C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl; or aminosulphonyl whereinthe amino group is optionally substituted by (C₁₋₄)alkyl or(C₂₋₄)alkenyl.

Each heterocyclic ring suitably has from 3 to 7, preferably 5 or 6, ringatoms. A fused heterocyclic ring system may include carbocyclic ringsand need include only one heterocyclic ring.

Compounds within the invention containing a heterocyclyl group may occurin two or more tautometric forms depending on the nature of theheterocyclyl group; all such tautomeric forms are included within thescope of the invention.

Where an amino group forms part of a single or fused non-aromaticheterocyclic ring as defined above suitable optional substituents insuch substituted amino groups include hydrogen; trifluoromethyl;(C₁₋₄)alkyl optionally substituted by hydroxy, (C₁₋₄)alkoxy,(C₁₋₄)alkylthio, halo or trifluoromethyl; and (C₂₋₄)alkenyl.

The term “heterocyclylalkyl” refers to a (C₁₋₆)alkyl radical which bearsas a substituent a heterocyclyl group, wherein heterocyclyl and alkylare as herein defined. The heterocyclyl group maybe joined to a primary,secondary or tertiary carbon of the (C₁₋₆)alkyl chain.

When used herein the term “aryl”, includes optionally substituted phenyland naphthyl.

Aryl groups may be optionally substituted with up to five, preferably upto three, groups selected from (C₁₋₄)alkylthio; halo; (C₁₋₄)haloalkoxy;(C₁₋₄)haloalkyl; (C₁₋₄)alkyl; (C₂₋₄)alkenyl; hydroxy;(C₁₋₄)hydroxyalkyl; (C₁₋₄)alkylthio; (C₁₋₄)alkoxy; nitro; cyano;carboxy; amino or aminocarbonyl optionally substituted by (C₁₋₄)alkyl;(C₁₋₄)alkylsulphonyl; (C₂₋₄)alkenylsulphonyl.

The term “aralkyl” refers to a (C₁₋₆)alkyl radical which bears as asubstituent an aryl group, wherein aryl and alkyl are as herein defined.The aryl group maybe joined to a primary, secondary or tertiary carbonof the (C₁₋₆)alkyl chain.

This invention also contemplates that some of its structural embodimentsmaybe present as a solvate. Solvates maybe produced from crstallizationfrom a given solvent or mixture of solvents, inorganic or organic.Solvates may also produced upon contact or exposure to solvent vapors,such as water. This invention includes within its scope stoichiometricand non-stoichiometric solvates including hydrates.

Furthermore, it will be understood that phrases such as “a compound ofFormula I or a pharmaceutically acceptable salt, solvate or derivativethereof” are intended to encompass the compound of Formula I, aderivative of formula (I), a pharmaceutically acceptable salt of thecompound of formula (I), a solvate of formula (I), or anypharmaceutically acceptable combination of these. Thus by way ofnon-limiting example used here for illustrative purpose, “a compound ofFormula I or a pharmaceutically acceptable salt or solvate thereof” mayinclude a pharmaceutically acceptable salt of a compound of formula (I)that is further present as a solvate.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach provided in substantially pure form, for example at least 60% pure,more suitably at least 75% pure and preferably at least 85%, especiallyat least 98% pure (% are on a weight for weight basis). Impurepreparations of the compounds may be used for preparing the more pureforms used in the pharmaceutical compositions; these less purepreparations of the compounds should contain at least 1%, more suitablyat least 5% and preferably from 10 to 59% of a compound of the formula(I) or pharmaceutically acceptable derivative thereof.

Pharmaceutically acceptable salts of the above-mentioned compounds offormula (I) include the free base form or their acid addition orquaternary ammonium salts, for example their salts with mineral acidse.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acids,or organic acids, e.g. acetic, fumaric, succinic, maleic, citric,benzoic, p-toluenesulphonic, methanesulphonic, naphthalenesulphonic acidor tartaric acids. Compounds of formula (I) may also be prepared as theN-oxide. Compounds of formula (I) having a free carboxy group may alsobe prepared as an in vivo hydrolysable ester. The invention extends toall such derivatives. One of skill in the art will recognize that wherecompounds of the invention contain multiple basic sites, a compound ofthe invention maybe present as a salt complexed with more than oneequivalent of a corresponding acid or mixture of acids.

Pharmaceutically acceptable derivatives refers to compounds of formula(I) that have been covalently modified with a group that undergoes atleast some in vivo cleavage to a compound of formula (I).

Examples of suitable pharmaceutically acceptable in vivo hydrolysableester-forming groups include those forming esters which break downreadily in the human body to leave the parent acid or its salt.

Suitable groups of this type include those of part formulae (i), (ii),(iii), (iv) and (v):

wherein R^(a) is hydrogen, (C₁₋₆) alkyl, (C₃₋₇) cycloalkyl, methyl, orphenyl, R^(b) is (C₁₋₆) alkyl, (C₁₋₆)alkoxy, phenyl, benzyl,(C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyloxy, (C₁₋₆)alkyl(C₃₋₇) cycloalkyl,1-amino(C₁₋₆)alkyl, or

1-(C₁₋₆alkyl)amino(C₁₋₆) alkyl; or R^(a) and R^(b) together form a1,2-phenylene group optionally substituted by one or two methoxy groups;R^(c) represents (C₁₋₆)alkylene optionally substituted with a methyl orethyl group and R^(d) and R^(e) independently represent (C₁₋₆) alkyl;R^(f) represents (C₁₋₆) alkyl; R^(g) represents hydrogen or phenyloptionally substituted by up to three groups selected from halogen,(C₁₋₆) alkyl, or (C₁₋₆) alkoxy; Q is oxygen or NH; R^(h) is hydrogen or

(C₁₋₆) alkyl; R^(i) is hydrogen, (C₁₋₆) alkyl optionally substituted byhalogen, (C₂₋₆) alkenyl, (C₁₋₆)alkoxycarbonyl, aryl or heteroaryl; orR^(h) and R^(i) together form (C₁₋₆) alkylene; R^(j) representshydrogen, (C₁₋₆) alkyl or (C₁₋₆)alkoxycarbonyl; and R^(k) represents(C₁₋₈)alkyl, (C₁₋₈)alkoxy, (C₁₋₆)alkoxy(C₁₋₆)alkoxy or aryl.

Examples of suitable in vivo hydrolysable ester groups include, forexample, acyloxy(C₁₋₆)alkyl groups such as acetoxymethyl,pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl,1-(cyclohexylcarbonyloxy)prop-1-yl, and (1-aminoethyl)carbonyloxymethyl;(C₁₋₆)alkoxycarbonyloxy(C₁₋₆)alkyl groups, such asethoxycarbonyloxymethyl, ethoxycarbonyloxyethyl andpropoxycarbonyloxyethyl; di(C₁₋₆)alkylamino(C₁₋₆)alkyl especiallydi(C₁₋₄)alkylamino(C₁₋₄)alkyl groups such as dimethylaminomethyl,dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;2-(C₁₋₆)alkoxycarbonyl)-2-(C₂₋₆)alkenyl groups such as2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl;lactone groups such as phthalidyl and dimethoxyphthalidyl.

A further suitable pharmaceutically acceptable in vivo hydrolysableester-forming group is that of the formula:

wherein R^(k) is hydrogen, C₁₋₆alkyl or phenyl.

R is preferably hydrogen.

Compounds of formula (I) may also be prepared as the correspondingN-oxides.

Certain of the compounds of formula (I) may exist in the form of opticalisomers, e.g. diastereoisomers and mixtures of isomers in all ratios,e.g. racemic mixtures. The invention includes all such form, includingpure isomeric forms. The different isomeric forms may be separated orresolved one from the other by conventional methods, or any given isomermay be obtained by conventional synthetic methods or by stereospecificor asymmetric syntheses.

One of skill in the readily appreciates that optimization for a givenreaction may require some routine variation in reaction parameters suchas reaction time, temperature, energy source, pressure, light, pressure,solvent or solvents used, co-reagents, catalysts, and the like.

Protective groups wherever found herein maybe designated by theirspecific formula or alternatively, maybe referred to generically by P orP_(n) (wherein n is an integer). It is to be appreciated that wheregeneric descriptors are used, that such descriptors are at eachoccurrence independent from each other. Thus, a compound with more thanone of the same generic descriptors (e.g. P) does not indicate that eachP is the same protective group, they maybe the same or different, solong as the group is suitable to the chemistry being employed. Whereprotection or deprotection is generically referred to, one of ordinaryskill in the art will understand this to mean that suitable conditionsare employed that will allow for the removal of the protecting group tobe removed while minimizing reaction at other positions of the molecule,unless otherwise indicated. Many protective groups and protective groupstrategies are known to those of skill in the art in maybe found innumerous references including, Greene, et al. “Protective Groups inOrganic Synthesis” (Published by Wiley-Interscience), which is hereinincorporated by reference in its entirety.

The antibacterial compounds according to the invention may be formulatedfor administration in any convenient way for use in human or veterinarymedicine, by analogy with other antibacterials.

The pharmaceutical compositions of the invention include those in a formadapted for oral, topical or parenteral use and may be used for thetreatment of bacterial infection in mammals including humans.

The composition may be formulated for administration by any route. Thecompositions may be in the form of tablets, capsules, powders, granules,lozenges, creams or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilized powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilization cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% by weight, preferably from 10-60%by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill preferably contain from 50-500 mg of the active ingredient. Thedosage as employed for adult human treatment will preferably range from100 to 3000 mg per day, for instance 1500 mg per day depending on theroute and frequency of administration. Such a dosage corresponds to 1.5to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

The compound of formula (I) may be the sole therapeutic agent in thecompositions of the invention or a combination with otherantibacterials. If the other antibacterial is a β-lactam then aβ-lactamase inhibitor may also be employed.

Compounds of formula (I) are active against a wide range of organismsincluding both Gram-negative and Gram-positive organisms.

The compounds of this invention may also be used in the manufacture ofmedicaments useful in treating bacterial infections in humans or othermammals.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference (whether specifically stated to be so or not) as if eachindividual publication were specifically and individually indicated tobe incorporated by reference herein as though fully set forth.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described herein above.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form, forexample, of product, composition, process, or use claims.

The following examples illustrate the preparation of certain compoundsof formula (I) and the activity of certain compounds of formula (I)against various bacterial organisms. Although specific examples aredescribed in the schemes, one of skill in the art appreciates that themethods are more generally applicable.

One of skill in the art readily appreciates that although the followingschemes describe specific examples, they maybe more generally applied toproduce additional embodiments of this invention. Furthermore, theexamples set forth below are illustrative of the present invention andare not intended to limit, in any way, the scope of the presentinvention.

The examples of this invention were prepared by the methods illustratedin Scheme I.

Reagents and conditions: (a) Boc₂O, CH₃CN-THF, 25° C. (b) O₃, MeOH-DCM;then BnNH₂, NaBH₃CN, MeOH, 0-25° C. (c) H₂ (50 psi), Pd(OH)₂, EtOH (d)8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine, EtOH, 85° C. (e) 4MHCl in dioxane, MeOH, 25° C. (f)3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde, Na₂SO₄,DCM-EtOH; then NaBH₄, 25° C. (g)3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde, Na₂SO₄,DCM-EtOH; then NaBH₄, 25° C.

7-Oxabicyclo[2.2.1]hept-5-en-2-amine (I-1, prepared according toHutchinson, S. A; et. al; Bioorg. Med. Chem. Lett. 1999, 9, 33.) wasprotected as the t-butylacetamide (I-2). Ozonolysis followed by in situreductive amination with benzylamine afforded the azabicycle (I-3). Thebenzyl group was removed through hydrogenolysis generating the freeamine (I-4), which subsequently underwent Michael addition into thevinyl substrate providing adduct (I-5). The Boc group was then removedunder the standard conditions as described by protection groupreferences like Kocienski or Greene. The resulting free amine wascoupled with the appropriate aldehyde through reductive aminationgenerating the chromatographically separable diastereomers (I-6, I-7).

General

Proton nuclear magnetic resonance (¹H NMR) spectra were recorded at 400MHz, and chemical shifts are reported in parts per million (δ) downfieldfrom the internal solvent standard CHCl₃ or MeOH. Abbreviations for NMRdata are as follows: s=singlet, d=doublet, t=triplet, q=quartet,m=multiplet, dd=doublet of doublets, dt=doublet of triplets,app=apparent, br=broad. J indicates the NMR coupling constant measuredin Hertz. CDCl₃ is deuterochloroform and CD₃OD is tetradeuteromethanol.Mass spectra were obtained using electrospray (ES) ionizationtechniques. All temperatures are reported in degrees Celsius. E. MerckSilica Gel 60 F-254 thin layer plates were used for thin layerchromatography. Flash chromatography was carried out on E. MerckKieselgel 60 (230-400 mesh) silica gel. Analytical HPLC was performed onBeckman chromatography systems. Preparative HPLC was performed usingGilson chromatography systems. ODS refers to an octadecylsilylderivatized silica gel chromatographic support. YMC ODS-AQ® is an ODSchromatographic support and is a registered trademark of YMC Co. Ltd.,Kyoto, Japan. PRP-1® is a polymeric (styrene-divinylbenzene)chromatographic support, and is a registered trademark of Hamilton Co.,Reno, Nev. Celite® is a filter aid composed of acid-washed diatomaceoussilica, and is a registered trademark of Manville Corp., Denver, Colo.

Stereochemical designations in the Examples refer to relativestereochemistry.

Preparation of 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine

(a) (2-[(6-Methoxypyridin-3-ylamino)methylene]malonic Acid Diethyl Ester

A solution of 5-amino-2-methoxypyridine (Aldrich, 100 g, 0.806 mole) anddiethyl ethoxymethylenemalonate (Aldrich, 163 mL, 0.806 mole) in EtOH (1L) was heated at reflux for 4 h, then was cooled to RT. Concentration todryness gave the title compound (238 g, quantitative).

(b) 6-Methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic AcidEthyl Ester

Dowtherm A (Fluka, 500 mL) was brought to boiling (250° C.) in a 2 L3-neck flask fitted with a still-head and a reflux condenser.2-[(6-Methoxypyridin-3-ylamino)methylene]malonic acid diethyl ester (100g, 0.34 mole) was added portion-wise over 5 min. The solution was heatedat reflux for an additional 15 min, allowing some solvent to distilover. The resulting solution was cooled to room temperature and dilutedwith hexane (750 mL). The mixture was cooled in ice for 1 h, then thebrown solid was filtered off, washed with hexane, and dried under vacuumto afford the title compound (61.72 g, 73%).

(c) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic Acid Ethyl Ester

A suspension of6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethylester (74.57 g, 300 mmol) in dry DMF (260 mL) under argon was stirredefficiently* in a water bath (to maintain approximately roomtemperature—may need slight ice-cooling on a large scale). Phosphorustribromide (30.0 mL, 316 mmol) was added dropwise over 15 min andstirring was continued for an additional 30 min. Water (1 L) was added,followed by saturated sodium carbonate solution to pH 7. The solid wascollected by suction filtration, washed with water and dried undervacuum over phosphorus pentoxide to give the title compound (83.56 g,90%).

(d) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic Acid

2 N NaOH (300 mL, 600 mmol) was added dropwise over 30 min to a stirredsolution of 4-bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethylester (83.56 g, 268 mmol) in THF (835 mL). Stirring was continuedovernight, at which time LC/MS showed that the saponification wascomplete. 2 N HCl was added to pH 6 and the THF was removed in vacuo. 2N HCl was added to pH 2, then water (250 mL) was added, and the mixturewas cooled thoroughly in ice. The solid was collected by suctionfiltration, washed with water and dried (first using a rotary evaporatorat 50° C. and then under high vacuum at 50° C. overnight) to give thetitle compound (76.7 g, slightly over quantitative). This material wasused without further purification.

(e) 4-Bromo-6-methoxy-[1,5]naphthyridin-3-ylamine

A suspension of 4-bromo-6-methoxy-[1,5]naphthyridine-3-carboxylic acid(50 g, 177 mmol) in dry DMF (600 mL) was treated with triethylamine(222.5 mL, 1.60 mole), tert-butanol (265 mL, 2.77 mole) anddiphenylphosphoryl azide (41.75 mL, 194 mmol). The reaction was stirredunder argon at 100° C. for 1 h, then was cooled to room temperature andconcentrated to low volume. Ethyl acetate and excess aqueous sodiumbicarbonate solution were added, the mixture was shaken, and someinsoluble solid was filtered off. The layers were separated and theorganic phase was washed with water (2×) and dried (MgSO₄).Concentration to dryness gave a crude mixture of4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine (minor product) and(4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine)carbamic acid tert-butylester (major product) along with impurities.

Without further purification, this mixture was dissolved in CH₂Cl₂ (150mL) and treated with trifluoroacetic acid (100 mL). The reaction wasstirred for 3 h then was concentrated to dryness. The residue waspartitioned between CHCl₃ and saturated sodium bicarbonate solution andthe layers were separated. The aqueous phase was extracted with CHCl₃,and the combined organic fractions were dried (MgSO₄) and concentratedto low volume. The solid was collected by suction filtration, washedwith a small volume of CHCl₃ and dried under vacuum to afford a firstcrop of the title compound (31.14 g). The filtrate was purified by flashchromatography on silica gel (30% EtOAc in CHCl₃) to afford furthermaterial (2.93 g, total=34.07 g, 76%). Alternatively, the filtrate wasleft at room temperature overnight and then filtered to give a secondcrop of the title compound (2.5 g).

(f) 4-Bromo-6-methoxy-[1,5]naphthyridine-3-diazonium tetrafluoroborate

A solution of 4-bromo-6-methoxy-[1,5]naphthyridin-3-ylamine (25.2 g,99.2 mmol) in dry THF (400 mL) was maintained at −5° C. whilenitrosonium tetrafluoroborate (12.9 g, 110 mmol) was added portion-wiseover 30 min (approximately 2 g portions). The reaction was continued foran additional 1 h at −5° C., at which time TLC* and LC/MS indicated thatthe reaction was complete. The orange solid was collected by suctionfiltration, washed with ice-cold THF and dried under vacuum to providethe title compound (31.42 g, 90%).

(g) 4-Bromo-3-fluoro-6-methoxy-[1,5]naphthyridine

A suspension of 4-bromo-6-methoxy-[1,5]naphthyridine-3-diazoniumtetrafluoroborate (31.42 g, 89.0 mmol) in decalin (mixed isomers, 500mL) in a 2 L flask* was heated to 180° C. and held at this temperaturefor 5 min. The mixture was cooled and diluted with CHCl₃ (500 mL, tokeep the product in solution), and the resulting mixture was stirredvigorously for 30 min to break up a black solid by-product. The mixturewas then poured onto a column of silica gel and the column was elutedwith CHCl₃ to remove decalin and then with 3% EtOAc/CHCl₃ to afford thetitle compound (9.16 g, 40%).

(h) 8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine

To a solution of 8-bromo-7-fluoro-2-(methyloxy)-1,5-naphthyridine (2.0g, 7.81 mmol), potassium carbonate (1.08 g, 7.81 mmol),tetrakis-triphenylphosphine (90 mg, 0.08 mmol) in DME (60 mL) and H₂O(20 mL) was added 2,4,6-trivinylcycloborane-pyridine complex (0.94 g,3.91 mmol). After stirring for 10 h at 85° C. the reaction contents wereconcentrated and the product purified by chromatography (silica, 25%EtOAc in hexane) to give a low melting solid (1.43 g, 90%).

Preparation of3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

(a) Methyl 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate

A solution of ethyl 2-mercaptoacetate (1.473 mL) in DMF (48 mL) wasice-cooled and treated with sodium hydride (540 mg of a 60% dispersionin oil). After 1 h methyl 6-amino-5-bromopyridine-2-carboxylate (3 g)(T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was addedand the mixture stirred for 16 h at room temperature. The solution wasdiluted with EtOAc (1 L), washed with water (3×300 mL), dried andevaporated to about 10 mL. The white solid was filtered off and washedwith a little EtOAc to give the ester (0.95 g); LC/MS (APCl⁻) m/z223([M-H]⁻, 100%).

(b) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid

A solution of Methyl3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylate (788 mg)in dioxan (120 ml)/water (30 mL) was treated dropwise over 2 h with 0.5MNaOH solution (8 mL) and stirred overnight. After evaporation to approx.3 ml, water (5 mL) was added and 2M HCl to pH4. The precipitated solidwas filtered off, washed with a small volume of water and dried undervacuum to give a solid (636 mg); LC/MS (APCl⁻) m/z 209 ([M-H]⁻, 5%),165([M-COOH]³¹, 100%).

(c) 6-Hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine

A solution of3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (500mg) in THF (24 mL) with triethylamine (0.396 mL) was cooled to −10° C.and isobutyl chloroformate (0.339 ml) was added. After 20 minutes thesuspension was filtered through kieselguhr into an ice-cooled solutionof sodium borohydride (272 mg) in water (8 mL), the mixture stirred 30minutes and the pH reduced to 7 with dilute HCl. The solvent wasevaporated and the residue triturated under water. The product wasfiltered and dried under vacuum to give a white solid (346 mg): LC/MS(APCl⁻) m/z 195 ([M-H]⁻, 50%), 165(100%).

(d) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde

A solution of6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine (330 mg)in dichloromethane (30 mL)/THF (30 mL) was treated with manganesedioxide (730 mg) and stirred at room temperature. Further manganesedioxide was added after 1 h (730 mg) and 16 h (300 mg). After a total of20 h the mixture was filtered through kieselguhr and the filtrateevaporated. The product was triturated with EtOAc/hexane (1:1) andcollected to give a solid (180 mg): LC/MS (APCl⁻) m/z 195 ([M-H]⁻, 95%),165 (100%).

Preparation of3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde

(a) 2-Bromo-5-hydroxy-6-nitropyridine

3-Hydroxy-2-nitropyridine (20 g, 0.143 mole) was dissolved in methanol(400 mL) and a solution of 25% sodium methoxide in methanol (33 mL, 0.13mole) was added at room temperature. The mixture was stirred for 30 min,then was cooled to 0° C., and bromine (7.2 mL, 0.14 mole) was addedslowly. The reaction was stirred at 0° C. for 30 min, then was quenchedwith glacial AcOH (2.5 mL). The solvent was removed in vacuo to affordmaterial (30 g, 96%), which was used without further purification: MS(ES) m/z 219.0 (M+H)⁺.

(b) Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate

2-Bromo-5-hydroxy-6-nitropyridine (30 g, 0.14 mole) was suspended inacetone (200 ml), and potassium carbonate (39 g, 0.28 mole) was added,followed by ethyl bromoacetate (15.7 ml, 0.14 mmole). The reaction washeated at reflux for 10 hr, then was cooled to room temperature anddiluted with Et₂O. The precipitate was removed by suction filtration,and the filtrate was concentrated in vacuo to afford material (38 g,89%), which was used without further purification: MS (ES) m/z 305.0(M+H)⁺.

(c) 6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one

Ethyl (6-bromo-2-nitro-pyridin-3-yloxy)acetate (38 g, 0.125 mole) wasdissolved in glacial AcOH (150 mL), and iron powder (20 g, 0.36 mole)was added. The mixture was mechanically stirred and heated at 90° C. for5 hr, then was cooled to room temperature and diluted with EtOAc (300mL). The mixture was filtered through a pad of silica gel and thefiltrate was concentrated in vacuo and the residue recrystallized fromMeOH (15 g, 52%): MS (ES) m/z 229.0 (M+H)⁺.

(d) 6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one

6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (6.0 g, 26.3 mmole) andtrans-2-phenylvinylboronic acid (3.9 g, 26.3 mmole) were dissolved in1,4-dioxane (150 mL) and the solution was degassed with argon. (Ph₃P)₄Pd(230 mg, 0.2 mmole) was added, followed by a solution of potassiumcarbonate (6.9 g, 50 mmole) in H₂O (20 mL). The reaction was heated atreflux under argon overnight, then was cooled to room temperature anddiluted with EtOAc (200 mL). The solution was washed sequentially withH₂O and brine, dried (Na₂SO₄), and concentrated in vacuo. The solidresidue was purified by flash chromatography on silica gel (5-10%EtOAc/CHCl₃) to afford a solid (2.5 g, 38%): MS (ES) m/z253.0 (M+H)⁺.

(e) 3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde

6-((E)-Styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.2 g, 4.8 mmole) wasdissolved in CH₂Cl₂ (200 mL) and the solution was cooled to −78° C.Ozone was bubbled through the solution with stirring until a pale bluecolor appeared, then the excess ozone was removed by bubbling oxygenthrough the solution for 15 min. Dimethylsulfide (1.76 mL, 24 mmole) wasadded to the solution, and the reaction was stirred at −78° C. for 3 hr,then at room temperature overnight. The solvent was removed in vacuo,and the residue was triturated with Et₂O (50 mL). The collected solidwas washed with additional Et₂O and dried to afford a solid (700 mg,82%): MS (ES) m/z 179.0 (M+H)⁺.

EXAMPLE 1

Preparation of(±)-6-{[((1R,5R,6S)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-8-oxa-3-azabicyclo[3.2.1]oct-6-l)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-oneand6-{[((1R,5R,6R)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

(a) 1,1-dimethylethyl 7-oxabicyclo[2.2.1]hept-5-en-2-ylcarbamate

To a solution of 7-oxabicyclo[2.2.1]hept-5-en-2-amine (3 g, 27.0 mmol,4:1 endo-exo) in THF/CH₃CN (150 mL, 4:1) at 25° C. was addedbis(1,1-dimethylethyl) dicarbonate (7.08 g, 32.4 mmol). After 0.5 h, thesolution was concentrated and the residue purified by columnchromatography (silica, 0-1% MeOH in DCM (1% NH₄OH)) affording the titlecompound as a sticky white solid (5.3 g, 93%): LC/MS (ES) m/e 212(M+H)⁺.

(b) 1,1-dimethylethyl[3-(phenylmethyl)-8-oxa-3-azabicyclo[3.2.1]oct-6-yl]carbamate

To a solution 1,1-dimethylethyl7-oxabicyclo[2.2.1]hept-5-en-2-ylcarbamate (1.0 g, 4.74 mmol) inMeOH/DCM (48 mL, 1:1) at −78° C. was bubbled through O₃ until thesolution maintained a blue color. N₂ was then bubbled through until theblue color dissipated and a solution of benzylamine (0.49 mL, 4.5 mmol)and NaBH₃CN (1.19 g, 19.0 mmol) in MeOH (22 mL) was added dropwise.After gradually warming to 25° C. over 12 hr, the mixture waspartitioned between 6N NaOH and DCM. The aqueous layer wasback-extracted several times with DCM and the combined organic fractionswere concentrated and purified by column chromatography (silica, 0-1%MeOH in DCM (1% NH₄OH )) affording the title compound as a clear oil(560 mg, 37%): LC/MS (ES) m/e 319 (M+H)⁺.

(c) 1,1-dimethylethyl 8-oxa-3-azabicyclo[3.2.1]oct-6-ylcarbamate

To a solution of 1,1-dimethylethyl[3-(phenylmethyl)-8-oxa-3-azabicyclo[3.2.1]oct-6-yl]carbamate (560 mg,1.76 mmol) in EtOH (18 mL) at 25° C. was added Pd(OH)₂ (336 mg, 60 wt%). The suspension was hydrogenated at 50 psi using a Parr Shaker. After12 h, the solution was filtered through Celite®, concentrated andpurified through a pad of silica (5% MeOH in DCM (1% NH₄OH)) affordingthe title compound (400 mg, quant.) as a white solid: LC/MS (ES) m/e 229(M+H)⁺.

(d) 1,1-dimethylethyl(3-{2-[2-fluoro-7-(methyloxy)-1-naphthalenyl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)carbamate

A solution of 1,1-dimethylethyl8-oxa-3-azabicyclo[3.2.1]oct-6-ylcarbamate (116 mg, 0.51 mmol) and8-ethenyl-7-fluoro-2-(methyloxy)-1,5-naphthyridine (104 mg, 0.51 mmol)in DMF (1 mL) was heated at 85° C. After 12 h, the solution wasconcentrated and the residue was purified via column chromatography(silica, 1-3% MeOH in DCM (1% NH₄OH)) yielding the title compound (350mg, 45%) as an orange oil: LC/MS (ES) m/e 434 (M+H)⁺.

(e)3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]octan-6-amine

To a solution of 1,1-dimethylethyl(3-{2-[2-fluoro-7-(methyloxy)-1-naphthalenyl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)carbamate(350 mg, 0.81 mmol) in MeOH (24 mL) at 25° C. was added dropwise a 4Msolution of HCl in dioxane (1.4 mL, 5.6 mmol). After 12 h, the reactionwas concentrated and neutralized with excess DIPEA in DCM. The resultingresidue was then purified through a pad of silica (5% MeOH in DCM (1%NH₄OH)) yielding the title compound (240 mg, 90%) as a yellow oil: LC/MS(ES) m/e 334 (M+H)⁺.

(f)(±)-6-{[((1R,5R,6S)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-oneand6-{[((1R,5R,6R)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H-one

To a solution of3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]octan-6-amine(240 mg, 0.72 mmol) in EtOH:DCM (8 mL, 1:1) were added Na₂SO₄ (154 mg,1.1 mmol) followed by3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (141 mg,0.72 mmol). After 12 h at 25° C., NaBH₄(43 mg, 1.1 mmol) was added.After an additional 1 h, the reaction was concentrated and the residuewas partitioned between DCM/H₂O. The combined organic fractions weredried over MgSO₄, concentrated and the diastereomers separated viacolumn chromatography (silica, 1-4% MeOH in DCM (1% NH₄OH)) yielding thetitle compounds as yellow solids: (β-amine, 10 mg, 2.7%); LC/MS (ES) m/e511 (M+H)⁺; ¹H NMR (CD₃OD, 400 Hz) δ 8.40 (s, 1H), 8.02 (d, J=9.0 Hz,1H), 7.51 (d, J=7.6 Hz, 1H), 7.02 (d, J=9.0 Hz, 1H), 6.71 (d, J=7.8 Hz,1H), 4.16-4.18 (m, 1H), 3.96-3.98 (m, 1H), 3.94 (s, 3H), 3.37-3.48 (m,5H), 3.25 (s, 2H), 2.95-2.98 (m, 1H), 2.81-2.85 (m, 2H), 2.75-2.80 (m,1H), 2.34-2.38 (m, 1H), 2.25-2.29 (m, 1H), 2.12-2.18 (m, 1H), 1.23-1.27(m, 1H). (α-amine, 30 mg, 8.2%); LC/MS (ES) m/e 511 (M+H)⁺; ¹H NMR(CDCl₃, 400 Hz) δ 8.57 (s, 1H), 8.20 (d, J=9.0 Hz, 1H), 7.69 (d, J=7.8Hz, 1H), 7.16 (d, J=9.1 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 4.32-4.34 (m,1H), 4.09 (s, 3H), 4.04-4.06 (m, 1H), 3.65 (s, 2 H), 3.52-3.61 (m, 2H),3.35-3.38 (m, 2 H), 2.96-2.99 (m, 1H), 2.72-2.80 (m, 3H), 2.64-2.67 (m,1H), 2.31 (d, J=10.9 Hz, 2H), 1.84-1.89 (m, 1H), 1.54-1.55 (m, 1H).

These compounds, as a solutions in MeOH, were treated with an excess of4M HCl in dioxane and evaporated to dryness to provide the correspondingdihydrochloride salts.

EXAMPLE 2

Preparation of(±)-6-{[((1R,5R,6S)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4 H)-one and6-{[((1R,5R,6R)-3-[2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4 H)-one

The title compounds were prepared according to Example 1, exceptsubstituting3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (270 mg,0.813 mmol) for3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde. Thediastereomers were then separated by column chromatography (silica, 1%MeOH in DCM (1% NH₄OH)) yielding the title compounds as yellow solids.

(β-amine, 25 mg, 8%); LC/MS (ES) m/e 495 (M+H)⁺; ¹H NMR (CD₃OD, 400 Hz)δ 8.51 (s,1H), 8.13 (d, J=9.1 Hz,1H), 7.20 (d, J=8.0 Hz, 1H), 7.14 (d,J=9.1 Hz, 1H), 6.76 (d, J=8.1 Hz, 1H), 4.72 (AB quart., 2H), 4.28-4.30(m, 1H), 4.09-4.1 (m, 1H), 4.05 (s, 3H), 3.47-3.57 (m, 3H), 3.32-3.34(m, 2H), 3.03-3.05 (m, 1H), 2.87-2.9 (m, 2H), 2.75-2.81 (m, 1H),2.46-2.5 (m, 1H), 2.37-2.42 (m, 1H), 2.26-2.33 (m, 1H), 1.39-1.42 (m,1H).

(α-amine, 100 mg, 25%); LC/MS (ES) m/e 495 (M+H)⁺; ¹H NMR (CD₃OD, 400Hz) δ 8.56 (s, 1H), 8.19 (d, J=9.1 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.15(d, J=9.1 Hz, 1H), 6.89 (d, J=8.1 Hz, 1H), 4.72 (AB quart., 2H),4.32-4.33 (m, 1H), 4.07 (s, 3H), 4.04 (s, 1H), 3.61 (s, 2H), 3.32-3.37(m, 2H), 2.96-2.98 (m, 1H), 2.64-2.79 (m, 4H), 2.29-2.33 (m, 2H),1.84-1.88 (m, 1H), 1.51-1.57 (m, 1H).

These compounds, as solutions in MeOH, were treated with an excess of 4MHCl in dioxane and evaporated to dryness to provide the correspondingdihydrochloride salts.

Example Structure Formula 1

(±)-6-{[((1R,5R,6S)-3-{2-[3-fluoro-6- (methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2- b][1,4]thiazin-3(4H)-one 2

(±)-6-{[((1R,5R,6R)-3-{2-[3-fluoro-6- (methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2- b][1,4]thiazin-3(4H)-one 3

(±)-6-{[((1R,5R,6S)-3-{2-[3-fluoro-6- (methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-one 4

(±)-6-{[((1R,5R,6R)-3-{2-[3-fluoro-6- (methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-one

EXAMPLE 5

Antimicrobial Activity Assay:

Whole-cell antimicrobial activity was determined by broth microdilutionusing the National Committee for Clinical Laboratory Standards (NCCLS)recommended procedure, Document M7-A6, “Methods for DilutionSusceptibility Tests for Bacteria that Grow Aerobically”. The compoundswere tested in serial two-fold dilutions ranging from 0.016 to 16mcg/mL.

Compounds were evaluated against a panel of Gram-positiye organisms,including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcuspyogenes, and Enterococcus faecalis.

In addition, compounds were evaluated against a panel of Gram-negativestrains including Haemophilus influenzae, Moraxella catarrhalis andEscherichia coli.

The minimum inhibitory concentration (MIC) was determined as the lowestconcentration of compound that inhibited visible growth. A mirror readerwas used to assist in determining the MIC endpoint.

One skilled in the art would consider any compound with a MIC of lessthan 20 mg/mL to be a potential lead compound. For instance, each of thelisted Examples (1 to 4), as identified in the present application, hada MIC≦20 mg/ml against at least one of the organisms listed above.

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof,

wherein: Z₁, Z₃, and Z₄ are independently N or CR^(1a); Z₂, Z₅, and Z₆are each CR^(1a); A is CR₂R₃; R₁ and R^(1a) are independently at eachoccurrence hydrogen; cyano; halo; hydroxy; (C₁₋₆)alkoxy; R₂ is hydrogen;halo; hydroxy; or (C₁₋₆)alkoxy; R₃ is hydrogen; R₈ is hydrogen; halo;hydroxyl; or (C₁₋₆)alkyl; R₁₁ is hydrogen, (C₁₋₆)alkyl,(C₁₋₆)alkoxycarbonyl, or (C₁₋₆)alkylcarbonyl; R₁₂ is UR₁₃; U is CH₂;C(═O); or SO₂; R₁₃ is a substituted or unsubstituted heterocyclic ringsystem (A):

X is O or S R₁₅ is at each occurrence independently hydrogen;(C₁₋₄)alkyl; (C₁₋₄)alkoxy; halo or trifluoromethyl.
 2. A compoundaccording to claim 1, wherein: Z₁ and Z₄ are N; and Z₃ is CR^(1a).
 3. Acompound according to claim 1, wherein: R₁ is OCH₃.
 4. A compoundaccording to claim 1, wherein: R^(1a) is at each occurrenceindependently hydrogen; halogen; or cyano.
 5. A compound according toclaim 4, wherein: R₁₅ is hydrogen.
 6. A compound or a pharmaceuticallyacceptable salt thereof, wherein the compound is selected from groupconsisting of3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one;6-{[((1R,5R,6R)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one;6-{[((1R,5R,6S)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;and6-{[((1R,5R,6R)-3-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-8-oxa-3-azabicyclo[3.2.1]oct-6-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one.7. A pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 8. A method of treating bacterialinfections due to Staphylococcus aureus, Streptococcus pneumoniae,Streptococcus pyogenes, Enterococcus faecalis, Haemophilus influenzae,Moraxella catarrhalis or Escherichia coil in mammals which comprisesadministering to a mammal in need thereof an effective amount of acompound of claim 1.